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Structure of Erm-modified 70S ribosome reveals the mechanism of macrolide resistance
Nature Chemical Biology ( IF 12.9 ) Pub Date : 2021-01-18 , DOI: 10.1038/s41589-020-00715-0
Maxim S Svetlov 1, 2 , Egor A Syroegin 3 , Elena V Aleksandrova 3 , Gemma C Atkinson 4 , Steven T Gregory 5 , Alexander S Mankin 1, 2 , Yury S Polikanov 1, 2, 3
Affiliation  

Many antibiotics inhibit bacterial growth by binding to the ribosome and interfering with protein biosynthesis. Macrolides represent one of the most successful classes of ribosome-targeting antibiotics. The main clinically relevant mechanism of resistance to macrolides is dimethylation of the 23S rRNA nucleotide A2058, located in the drug-binding site, a reaction catalyzed by Erm-type rRNA methyltransferases. Here, we present the crystal structure of the Erm-dimethylated 70S ribosome at 2.4 Å resolution, together with the structures of unmethylated 70S ribosome functional complexes alone or in combination with macrolides. Altogether, our structural data do not support previous models and, instead, suggest a principally new explanation of how A2058 dimethylation confers resistance to macrolides. Moreover, high-resolution structures of two macrolide antibiotics bound to the unmodified ribosome reveal a previously unknown role of the desosamine moiety in drug binding, laying a foundation for the rational knowledge-based design of macrolides that can overcome Erm-mediated resistance.



中文翻译:

Erm修饰的70S核糖体的结构揭示了大环内酯类耐药的机制

许多抗生素通过与核糖体结合并干扰蛋白质生物合成来抑制细菌生长。大环内酯类药物是最成功的核糖体靶向抗生素之一。大环内酯类耐药的主要临床相关机制是位于药物结合位点的 23S rRNA 核苷酸 A2058 的二甲基化,该反应由 Erm 型 rRNA 甲基转移酶催化。在这里,我们以 2.4 Å 分辨率呈现 Erm-二甲基化 70S 核糖体的晶体结构,以及未甲基化 70S 核糖体功能复合物单独或与大环内酯组合的结构。总而言之,我们的结构数据不支持以前的模型,相反,对 A2058 二甲基化如何赋予对大环内酯类药物的抗性提出了一个主要的新解释。而且,

更新日期:2021-01-18
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